Faculty Collaboration Database

An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study. Gastroenterology 2022 Nov;163(5):1252-1266.e2

Date

07/20/2022

Pubmed ID

35850192

Pubmed Central ID

PMC9613527

DOI

10.1053/j.gastro.2022.06.090

Scopus ID

2-s2.0-85138796559 (requires institutional sign-in at Scopus site)   148 Citations

Abstract

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC.

METHODS: Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays.

RESULTS: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone).

CONCLUSIONS: In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

Author List

Nakamura K, Zhu Z, Roy S, Jun E, Han H, Munoz RM, Nishiwada S, Sharma G, Cridebring D, Zenhausern F, Kim S, Roe DJ, Darabi S, Han IW, Evans DB, Yamada S, Demeure MJ, Becerra C, Celinski SA, Borazanci E, Tsai S, Kodera Y, Park JO, Bolton JS, Wang X, Kim SC, Von Hoff D, Goel A

Author

Douglas B. Evans MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Biomarkers, Tumor
CA-19-9 Antigen
Carbohydrates
Carcinoma, Pancreatic Ductal
Cohort Studies
Exosomes
Humans
MicroRNAs
Pancreatic Neoplasms
Transcriptome